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Guidance on Formulating Compressed Solids
Published in Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations, Third Edition, 2019
Micronization, where possible, allows increase in the surface area to the maximum, which can impact on the solubility, dissolution, and as a result, bioavailability. Since the aim of most preformulation studies is to determine if a solid dosage form can be administered, knowing that reduction of particle size, where it changes dissolution rates, can be pivotal in decision making for the selection of dosage forms. In the process of micronization, the drug substance is fed into a confined circular chamber, where it is suspended in a high-velocity stream of air. Interparticulate collisions result in a size reduction. Smaller particles are removed from the chamber by the escaping air stream toward the center of the mill, where they are discharged and collected. Larger particles recirculate until their particle size is reduced. Micronized particles are typically less than 10 μm in diameter. In some instances, micronization can prove counterproductive, where it results in increased aggregation (leading to reduced surface area) or alteration of crystallinity, which must be studied using such methods as microcalorimetry, dynamic vapor sorption (DVS), or inverse gas chromatography (IGC).
Milling and Blending: Producing the Right Particles and Blend Characteristics for Dry Powder Inhalation
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Bernice Mei Jin Tan, Lai Wah Chan, Paul Wan Sia Heng
Milling and blending can be viewed as complementary techniques for the preparation of inhalable particles for DPI. Due to the inherent physicochemical and solid-state properties of micronized particles, such irregular morphologies, high surface energy and poor flow, it is almost always necessary to formulate them with a carrier. Jet milling remains as the micronization technique of choice for commercial applications due to its milling efficiency, low temperature environment, high throughput, and containment systems. While milling-induced amorphization is a true concern in any size reduction process, proper optimization of milling parameters or conditioning of drug may reduce its effect on product stability. Compared to milling of drug, blending of interactive mixtures is significantly more complex. In addition to blend uniformity, blending may be used to control the CAB in the interactive mixtures. Various options in formulation and blending techniques include: blending with force-control agents, modification of blending order, selection of blender design, and optimization of the speed and time of blending. Researchers have not reached a consensus on the impact of the above-mentioned variables on DPI performance. This is because the blending outcomes are also highly dependent on formulation variables, such as carrier particle size, surface properties, drug cohesiveness and adhesiveness, drug load, carrier to drug ratio, amorphous content, and many more. The inclusion of a ternary excipient adds further complexity to formulation design. Continued experimentation and optimization of milling and blending processes will allow for more efficient yet simplified ways to improve manufacturing and product performance.
Solubility and Dissolution Rate
Published in Ko Higashitani, Hisao Makino, Shuji Matsusaka, Powder Technology Handbook, 2019
Micronization is one of the simplest and most popular methods of improving the solubilizing properties of materials. As described in 2.15.1, an increase in the effective surface area facing a solvent effectively increases the dissolution rate; extremely fine particles less than ca. 1 μm can increase solubility compared with coarse particles of the same material. However, micronized particles tend to aggregate, and as a result their dissolution rates are sometimes slower than before micronization because of the decrease in effective surface area facing the dissolution medium under pharmaceutical dissolution test conditions.
Prediction of particle size distribution of dronedarone hydrochloride in spiral jet mill using design of experiments
Published in Chemical Engineering Communications, 2018
Šimo Kordić, Gordana Matijašić, Matija Gretić
According to the Biopharmaceutics Classification System (BCS), drugs classified as Class II are poorly water-soluble but have high intestinal permeability. Bioavailability of those drugs is controlled by their permeation rate (Han et al., 2011). Dronedarone hydrochloride is highly soluble in ethanol but poorly soluble in aqueous medium (according to JUSTIA Patents, 2004, negligible at pH values greater than 5), as almost half of the substances produced in pharmaceutical industry (Hu et al., 2004). Mahapatra et al. (2014) showed that dissolution of dronedarone hydrochloride can be enhanced by complexation with β-cyclodextrin and hydroxypropyl β-cyclodextrin. However, micronization is a conventional technique for the particle size reduction. It is commonly used to increase the solubility of active pharmaceutical ingredients, especially those classified as BCS Class II (Leleux and Williams, 2013). Micronization does not increase the equilibrium solubility of the drug itself, but it increases the dissolution rate by increasing the surface area (Khadka et al., 2014). Benkic et al. (2012) claim that the solubility of dronedarone or its pharmaceutically acceptable salt, in particular dronedarone hydrochloride, can also be sufficiently increased by micronization. It was also found (Benkic et al.) that the particle size of dronedarone or its pharmaceutically acceptable salt for tablet production is x90 < 20 µm or x90 < 15 µm and more preferably x90 < 6 µm.
Effect of a micronization method on the particle-size distribution and eluted phosphate-ion concentration for methane fermentation residue sludge
Published in Cogent Engineering, 2022
Takamasa Mori, Yui Komiya, Mitsuyasu Yabe
Considering the feature of ball milling and ultrasonication of the methane fermentation sludge, a possible process for producing liquid fertilizer is proposed. First, the methane fermentation sludge is micronized by ball milling, and then further micronized by ultrasonication, obtaining a liquid fertilizer with a solid particle size below 100 µm, which corresponds to the nozzle diameter of a boom sprayer, and a high phosphate-ion concentration. Careful process design, including the optimization of the ultrasonication and ball milling conditions, and the appropriate combination of these micronization techniques, is necessary for practical applications.